16alpha,17alpha-dihydroxypregnen-20-one derivatives



Unitcdstltes e I 2,121,909

Patented Dec. 20, 1955 of A -p regnen-3-ols and their esters I prefer touse as starting materials the 5,6-dibrorno compounds of the type2,727,909 16,17a-DlHYDROXYPREGNEN-20-ONE 5 DERIVATIVES CH co Frank B.Colton, Chicago, Ill., assignor to G. D. Searle & Co., Chicago, 111., acorporation of Illinois No Drawing. Application October 12, 1954,

Serial No. 461,925

6 Claims. (Cl. 260-3974) Br The present invention relates to a new groupof 16a,17otdihydroxypregnen-ZO-one derivatives and, morespecificalwherein R ehydmgen aeyl grouP- 1y, to compounds which can berepresented by the general An alternatllfe for the Preperaflen of the estructural formula I 20-ones of my invention are the1r phenylhydrazoneswhich are synthesized by a procedure developed by R. M. Dod- CHI 20 son.Thus a 16a,l7a-oxidopregnen-20-one of the type CH3 v CH3 0 a CH: )K HCH3 if.--

-OR o n A B is treated with an aryl hydrazine of the formula X Ar-NHNH2(such as phenylhydrazine) and a lower alkanoic acid of the type R-COOH(such as acetic acid) wherein one of the bonds linking the carbon atomsin to yield the corresponding phenylhydrazone of 16z-alposition 5 to thecarbon atoms in positions 4 and 6 is unkenoyloxy'Hwhydmxypregnenaofineef the type saturated, wherein R is a member of the class consisting CH:of hydrogen and (lower alkyl)-CO radicals and wherein C=N NH AI X: is amember of the class consisting of 0x0, 0 3 L.

HO 40 which can be deesterified to the phenylhydrazone of a and I16a,17a-dihydroxypregnen-ZO-one of the type B I CH3 (lower aflwD-C 0Oradicals CH I =IgNHAr 3 The lower alkyl radicals mentioned herein can bemethyl,

ethyl, straight and branched chain propyl, butyl, amyl, hexyl,cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclofiig cyclopemylpropylcyclohexylethyl and the These phenylhydrazones can be converted to thefree In the application Serial No. 393,214, filed November f P bycleavage with a mixture acetic 19, 1953, Chinn and Thielen havedescribed a series of anggymvle f h a1 bl h16/8,]7a-dihydroxy-20-ketopregnenes which they prepared 3 S o my i Ionave v e by treatment of a 16a,l7-oxido-20-ketopregnene with a monal andFardlovasqular activity and are Pamculafly of lower alkanoic acid. Chinnand Thielen indicated in i fi y i ifi furth d th their application thattheir compounds are the 16,8-epimers e owlfig f ustra.te m of thecompounds obtained by applicant by the treatment compolm s W m commutemy mventlon all me o s of the corresponding A -pregnenes with onemolecular for F i F e F i to be equivalent of osmium tetroxide in asolvent such as ether sawed as hmlltmg the i g m R? or q In or tertiarybutanol, followed by deosmylation with sodium t ese exam? es quanmles{natfm "F m mate "i sulfim This process can be depicted structurally asparts by weight, temperature 1s lndicated in degrees centifou'ows: gradeand optical rotations are determined at 25 C.

CH1 CH3 Example 1 To asolution of 7.4 parts of4,l6-pregnadiene-3,20-dione CE; CH3 in 430 parts of anhydrous ethermaintained at 0 C. are

OK added 6.1 parts of osmium tetroxide in 143 parts of an- D hydrousether. The reaction mixture is maintained at room temperature for a day,after which the greenish Y brown precipitate is collected on a filterand dissolved in In the preparation of 16a,l7a-dihydroxy-4-pregnene- 700parts of ethanol and 200 parts of water. This solu- 3.20-dione thereaction can be carried out directly without tion is heated to refluxand then treated with 35 parts of protection of the double bond in ringA. For the synthesis sodium sulfite and 300 parts of water. Refluxing iscontinned for'2'hours after which the mixture is concentrated undervacuum toabout-550parts and extractedwith ethylacetate. The extract isdried over anhydrous sodium sulfate, filtered and taken to dryness undervacuum. The crystalline'residue is dissolved in a %solution of ethylacetatein'benzene' and thus applied to'a chromatography columncontaining 500 parts of silica gel. The column is washed with 10, 15,and 20% solutions of ethyl acetate in benzene and theneluted with 4050%solutions of ethyl acetate in benzene. These eluates are evaporatedunder vacuum and the residue is extracted with ethyl acetate. Theextract is dried over anhydrous sodium sulfate, filtered and evaporated.The residue is crystallized first from a mixture of ethyl acetateinpetroleum ether and then from aqueous methanol. Thel6a,l7a-dihydroxy-4- pregnene-3,20-dione melts at about 182-184 C. Ithas the structural formula This compound melts at about 2l5-2l8 C. Thespecific rotation of a 5% chloroform solution is +88.

Example .2

An anhydrous mixture of 12 parts of 3-acet0xy-5,l6- pregnadien-ZO-one in500 parts of chloroform and 20 parts of potassium acetate in 200 partsof acetic acid is stirred at 0 C. for 3.5 hours while asolution of 5.6parts of bromine in 120 parts of glacial acetic acid is added dropwise.The chloroform solution is washed successively with sodium bicarbonatesolution and water, dried over anhydrous calcium sulfate and thenconcentrated under vacuum.

To a solution of 24.5 parts of 3-acetoxy-5,6-dibromo4,16-pregnadien-20-one in800 parts of anhydrous ether maintained at 0C., there are added 12.2 parts of osmium tetroxide in 280 parts ofether. The reaction mixture is maintained at 20 C. for 15 hours, afterwhich theprecipitate is. collected on a filter and dissolved in 2000partsof 80% ethanol. This solution is heated at reflux and then treatedwith a solution of 70 parts of sodium sulfite in 600 parts of water and100 parts ofzinc. Refluxingis continued for 1 hour after which themixture is filtered ,and

then concentrated to about one-third of its original volume and.extracted..with ethyl acetate.v This extract is. dried over anhydrouscalcium sulfate, filtered and taken to drywhich;recrystaliizedlfrom.acetone and cyclohexane, melts 4 at about 224-225C., resolidifies and then remelts at 243- 248 C. It has thestructuralformula 7 Further elution of'the column as in the precedingexample yields a D-homo rearrangement product, the 1,3,8- trihydroxy10a,l2a dimethyl' 1,2,3,4,4a,4b,5,7,8,9,10,l0a,l0b,ll,12,12a-hexadecahydrochrysen-Z-one which has the structuralformula CHt -'-OH Example 3 A mixture of 1 part of3,8,16a,17oi-trihydroxy-5-pregnen- 20-one, 50 parts of pyridine and 53parts of acetic anhydride is maintained at 25 C. for 12 hours and thendiluted with ice. The precipitate is collected on a filter, washed withwater, and crystallized repeatedly from a mixture of The'3fi,6a-diacetoxy-l7a-hy-" acetone and cyclohexane.droxy-S-pregnen-ZO-one thus obtained melts atabout 2l3- 215 C. It. hasthe structural formula Substitution of-82' parts of butyric anhydridefor the acetic 'anhydride used'inthe. foregoing process yields theCHa-OHz-CHr-C O O The infrared absorption spectrum of this compoundshows maxima at 2.84, 5.80, 5.89, 7.30 and 7.42 microns.

Example 4 resulting precipitate is. collected on the filter, washed with67% acetic acid and crystallized from dilute methanol.-

acetate in benzene.

An additional yield is obtained by concentration of the acetic acidmother liquor. The phenylhydrazone of 16aacetoxy-33,l7wdihydroxy-S-pregnen-ZO-one thus obtained melts at about 222223 C.to an orange melt with decomposition.

Example 5 A mixture of 200 parts of the phenylhydrazone of 16a:-acetoxy-3fi,17u-dihydroxy-5-pregnen-20-one and 200 parts of sodiummethoxide is heated on the steam bath in an open vessel for 30 minutesand then diluted with water until it becomes cloudy. After cooling theprecipitate is collected on a filter and recrystallized from a mixtureof acetone and cyclohexane. The phenylhydrazone of3B,16a,17a-trihydroxy-5-pregnen-20-one is thus obtined in White crystalsmelting at about 208.5209.5 C. to a yellow melt with decomposition.

Example 6 A mixture of 5 parts of the phenylhydrazone of35,1611,17m-trihydroxy-5-pregnen-2O-one, 525 parts of glacial aceticacid, 90 parts of water and 5 parts of pyruvic acid is stirred forhours. The mixture is then diluted with Water, the precipitate collectedon a filter and crystallized from acetone. The3,6,16a,17a-trihydroXy-5-pregnen--one thus obtained melts at about224225 C., resolidifies and melts again at about 244-247" C. Thecompound has the structural formula Example 7 A mixture of 1 part of thephenylhydrazone of 16aacetoxy-3fl,17a-dihydroxy-5-pregnen-20-one, 50parts of pyridine and 55 parts of acetic anhydride in maintained at roomtemperature for 15 hours and then diluted with ice. The precipitate iscollected on a filter and crystallized from dilute methanol. Thephenylhydrazone of the 3,8,16u-diacetoxy-17a-hydroxy-5-pregnen-20-onethus obtained melts at about 216-217 C. with decomposition. Theultraviolet absorption spectrum shows a maximum at 273.5 millimcronswith a molecular extinction coeificient of 23,500. The identical productis obtained by reaction of 2.7 parts of the phenylhydrazone of3,8,16a,17 x-trihydroxy-S-pregnen-ZO-one, 100 parts of pyridine and 105parts of acetic anhydride under the foregoing conditions.

Example 8 A solution of 5 parts of the phenylhydrazone of 35,16adiacetoxy 170: hydroxy 5 pregnen 20- one, 800 parts of glacial aceticacid, 150 parts of water, and 1 part of pyruvic acid is permitted tostand at room temperature for 15 hours. The reaction mixture is filteredand the filtrate is diluted with water. The precipitate is collected ona filter, dried in air and then applied in benzene solution to achromatography column containing 200 parts of silica gel. The column iswashed with benzene, 2% and 5% solutions of ethyl acetate in benzene andthen eluted with a 10% solution of ethyl This eluate is concentrated andcrystallized from dilute acetone to yield318,16a-diacetoxyl7a-hydroxy-5-pregnen-20-one melting at about 212.5214.5 C.

What is claimed is:

l. A compound of the structural formula wherein one of the bonds linkingthe carbon atom in position 5 to the carbon atoms in positions 4 and 6is unsaturated, wherein R is a member of the class consisting ofhydrogen and (lower alkyl)CO radicals and wherein X: is a member of theclass consisting of oxo,

(lower a1kyl)C O OW 5. A compound of the structural formula 6. Theprocess of preparing 16a,17a-dihydroxy-4- pregnene-3,20-dione whichcomprises oxidizing 4,16- pregnadien-3,20-dione with osmium tetroxide.

References Cited in the file of this patent UNITED STATES PATENTS2,265,143 Butenandt Dec. 9, 1941 2,602,804 Kendall July 8, 19522,666,770 Wall Jan. 19, 1954 2,683,712 Hogg July 13, 1954 2,684,364Jones July 20, 1954

1. A COMPOUND OF THE STRUCTURAL FORMULA